TESTS OF THE DOUBLE-STRAND BREAK, LETHAL POTENTIALLY LETHAL AND REPAIR-MISREPAIR MODELS FOR MAMMALIAN-CELL SURVIVAL USING DATA FOR SURVIVALAS A FUNCTION OF DELAYED-PLATING INTERVAL FOR LOG-PHASE CHINESE-HAMSTER V79 CELLS

Our data (Reddy et al., Raniat. Res. 141, 252-258, 1995) on the kineti cs of the repair of potentially lethal damage in log-phase Chinese ham ster V79 cells are used to test some predictions which arise from the different assumptions of the repair-misrepair (RMR) (C. A. Tobias, Rad iat. Res. 104, S77-S95, 1985), lethal-potentially lethal (LPL) (S. B. Curtis, Radiat. Res. 106, 252-270, 1986) and double-strand break (DSB) (J. Y. Ostashevsky, Radiat. Res. 118, 437-466, 1989) models. The LPL model defines the time available for repair of PLD (t(rep)) as the tim e taken to reach maximal survival in a delayed-plating recovery experi ment. Those data show that after this time has elapsed, contrary to th e expectation of the LPL model, survival can be increased by changing the medium used for delayed plating from fresh growth medium to condit ioned medium. According to the RMR model, all potentially lethal lesio ns should also be committed by that time and be unavailable for repair in the new medium. Only the DSB model correctly predicted that PLD (= DSBs) would still be available for repair after that time. Second, da ta for split-dose recovery are used to predict the first-order kinetic s time constant for DSB repair (tau(DSBR)) using the DSB model (24 +/- 1.5 min). This value is nearly identical to the value of 27 +/- 1 min determined from the data obtained by Cheong et al. using pulsed-field gel electrophoresis (PFGE) (Mutat. Res. 274, 111-122, 1992). The valu e based on PFGE is used to calculate the value of t(rep) predicted by the DSB model (2.6 +/- 0.1 h), which agrees with the value determined experimentally as the time when changing the delayed-plating medium fr om growth medium to conditioned medium no longer gives the full recove ry seen with delayed plating in conditioned medium (2.5 h). However, s ome recovery was seen for a change in the medium (growth medium to con ditioned medium) up to 5-6 h postirradiation. Reanalysis of the origin al data on DSB repair shows that they are consistent with two first-or der repair rates (18 +/- 7 min and about 52 min). These results are co nsistent with two pools of DSBs (or cells), each with their own t(rep) . The early t(rep), associated with tau(fast), is predicted to be 1.7 +/- 0.7 h, and the late t(rep), associated with tau(slow), is predicte d to be about 5 h. Both values are in excellent agreement with the tim es at which changing from growth medium to conditioned medium no longe r gives the full recovery seen in conditioned medium only (the early t (rep)), and the time when changing from growth medium to conditioned m edium produces no further increase in survival (the late t(rep)), resp ectively. It is noted that attempts to correlate radiosensitivity with the rates of DSB repair, rather than using an explicit model such as the DSB model, are unlikely to be productive since survival depends on both tau(DSBR) and t(rep) (as defined in the DSB model) and the latte r may be the more important determinant of radiosensitivity (as it app ears to be for ataxia telangiectasia cells compared to normal fibrobla sts and for irs compared to V79 cells). (C) 1997 by Radiation Research Society.